CFS is an illness of unknown etiology, often associated with sudden onset, flu-like symptoms, debilitating fatigue, low-grade fever, myalgia and neurocognitive dysfunction. CFS patients typically display reduced Karnofsky performance scores (KPS). The Karnofsky performance test measures an individual's ability to function and carry on normal activities. Karnofsky scores range form zero for a dead patient to 100 for no evidence of disease. Diagnosis of CFS remains one of exclusion.
An accumulating body of evidence suggests that CFS is associated with disregulation of both humoral and cellular immunity, including mitogen response, reactivation of viruses, abnormal cytokine production, diminished natural killer cell function and changes in intermediary metabolites. It has been suggested that the clinical and immunological abnormalities observed in CFS might include defects in the double-stranded RNA (dsRNA)dependent, interferon-inducible pathways, i.e., the 2',5'-oligoadenylate (2-5A) synthetase/RNase L and p68 kinase (PKR) antiviral defense pathways (Suhadolnik et al., Clin. Infect. Dis. 18:S96-S104, 1994; Suhadolnik et al., In Vivo 8:599-604(1994). The 2-5A synthetase/RNase L pathway is part of the antiviral defense mechanism in mammalian cells; this pathway also has a role in the regulation of cell growth and differentiation (Lengyel, Ann. Review Biochem. 51:251-282, 1982; Sen et al., Adv. Virus Res. 42:57-102, 1993).
When activated by dsRNA, 2-5A synthetase converts ATP to 2',5'-linked oligoadenylateswith 5'-terminal phosphates. Biologically active 2-5A binds to and activates a latent endoribonuclease, RNase L, which hydrolyzes single-stranded viral and cellular RNA, primarily after UpNp sequences, thereby inhibiting protein synthesis.
Previous studies on the 2-5A synthetase/RNase L pathway in CFS revealed a statistically significant dysregulation in which the 2-5A synthetase is present predominantly in its activated form, bioactive 2-5A levels are elevated, and RNase L activity is upregulated (Suhadolnik et al., Clin. Infect. Dis., supra; Suhadolnik et al., In Vivo, supra). Expression of the serine-threonine kinase, PKR, is downregulated in CFS (Suhadolnik et al., In Vivo, supra). PKR controls initiation of protein translation through phosphorylation of elF-2.
Despite these efforts, a clear cut molecular marker for CFS has not been identified. Diagnosis is presently carried out with resort to criteria recommended by the Centers for Disease Control and Prevention (Fukuda et al., Ann. Intem. Med. 121:953-959, 1994). What is needed is a biochemical test, relying on an unambiguous molecular markers for CFS, which may form the basis of a definitive CFS diagnosis, or which may be employed as an adjunct to other CFS diagnostic methods.